J . Am. Chem. SOC.1990, I 12, 4399-4403 Methvleaeoxocane 67: IH N M R (500 MHz, CDCId b 7.18-7.30 (m, 5 H, PhH), 4.34 and 4.15 (s, 1 H each, = C H h 3 . 9 i ( m , 1 H, OCH), 2.83-2.89 and 2.65-2.71 (m, 1 H each, PhCHA 2.23-2.36 (m, 2 H, =CIORKH,). 1.90-1.94 (m. 1 H).1.60-1.80 (m. 6 H). 1.22-1.50 (m. 2 Hj,0.91 (d:'j= 6.9 Hz,'3 H, CH,): MS (El, 70 eV) m/e 244.1814
(M, 2* 244'187 for C17H240)* 226 (3)7 186 (8)* 153 (6), 139 (I2)* 117 (21), 104 (53). 91 (100). 71 (34), 55 (17).
Acknowledgment. Support of this research by NSF Grant
4399
CHE-86-18451 is aratefullv acknowledged. NMR and mass spectra were deternhed at irvine with sr;kctrometers purchased with the assistance of NSF Shared Instrumentation Grants.
Supplementary Material Available: Experimental procedures and characterization data for the preparation of alcoho] and mixed-acetal cvclization Drecursors (2 . 1 Danes). Ordering information is given on any current masthead page.
-
.-,
Formation of A4-Oxocenes from Lewis Acid Promoted Cyclizations of 5-Hexenyl Acetals. Evidence for a Concerted Ene Cyclization Mechanism Todd A. Biumenkopf,' Gary C. Look, and Larry E. Overman* Contribution from the Department of Chemistry, University of California, Iruine, Iruine, California 9271 7 . Received November 29, 1989
Abstract: Both the intermolecular (kinetic) and intramolecular (product) hydrogen-deuterium isotope effects were determined (20) from the SnCI,-promoted cyclization of acetals to be 1.65 for the formation of 2-methyl-4-(trimethyIsilyl)-A4-oxocene 19,30, and 31 (eq 6). In other experimentssilyl acetal 32 was found to cyclize in the presence of SnCI4to form the silyl-A4-oxocene 34 and the alkylideneoxepane 35 in 2:l ratio (eq 7). Both results provide strong evidence that the formation of 4-(trimethylsilyl)-A4-oxocenes from SnCI,-promoted cyclizations of 5 4 trimethylsilyl)-5-hexenylacetals takes place by a concerted intramolecular ene mechanism. Also reported are SnCI,-promoted exchange reactions of formaldehyde- and aldehyde-derived acetals, which occur readily at -10 to 0 OC and -70 O C , respectively (eqs 2 and 3).
In the preceding paper we detailed our exploratory investigations of the preparation of A4-oxocenesfrom the Lewis acid promoted High regia- and stecyclization of 5-hexenyl acetals (eq A
Scheme I
R
R"
Rd
,
3
5
2
reoselectivity are hallmarks of this direct route to unsaturated eight-membered-ring ethers. In all of the cyclization reactions that we have studied, only the A4-oxoceneregioisomer is produced. This regiochemical outcome would be expected if the transformation of 1 2 occurred by a concerted intramolecular Alder ene reaction (Scheme I).3*4 Alternatively, as we discussed briefly in the preceding paper, a stepwise process (3 4 5) could also afford the A4 isomer regioselectively as a result of transannular deprotonation of the 4-oxocanyl cation 4.5-s
-
R
R
--
4
Scheme I1
( I ) NIH NRSA Postdoctoral Fellow (GM 09444),1984-1986. Present address: Division of Organic Chemistry, Burroughs Wellcome Co., 3030 Cornwallis Rd., Research Triangle Park, NC 27709. (2) Blumenkopf, T. A.; Bratz, M.;Castaleda, A.; Look, G. C.; Overman, L. E.; Rodriguez, D.; Thompson, A. S . J . Am. Chem. Sm., preceding paper
in this issue. (3) For reviews of the ene reaction, see: Hoffmann, H. M. R. Angew. Chem., In?. Ed. Engl. 1%9,8,556. Snider, 8. B. Acc. Chem. Res. 1980,13, 426. Whitesell. J. K. Ibid. 1985, 18, 280. (4) For reviews of intramolecular ene reactions, see: (a) Oppolzer, W.; Snieckus, V. Angew. Chem., In?. Ed. Engl. 1978,17,476. (b) Taber. D. F. ln?ramolecular Diels-Alder and Alder Ene Reactions: Springer-Verlag: Berlin, 1984. ( 5 ) Homoallylic alcohols are also formed predominantly in bimolecular Prins reactiom6 This selectivity has been ascribed to a concerted ene mechanism) or rationalized by oxygen participation in removal of the distal &hydrogen of a carbenium ion intermediate.
0002-7863/90/ 15 12-4399$02.50/0
In this paper we report our investigations of the timing of C-C bond formation and C-H bond cleavage in the Lewis acid pro(6) For reviews, see: Adams, D. R.; Bhatnagar, S.P. Synthesis 1977,661. Roberts, C. W. In Friedel-Crafts and Related Reactions; Olah, G . A,, Ed.; Interscience: New York, 1964; Vol. 2, Part 2, p 1175.
0 1990 American Chemical Society
Blumenkopf et al.
4400 J . Am. Chem. Soc., Vol. I 12, No. I I , 1990 Table 1. SnCI,-Promoted Exchange of Formaldehyde Acetals 6 and 7'
acetal composition?& % acetal rec.6 % 6 7 8 9 10 11 12 0 (100) 50 50 5 49 17 70 IO 1 2 30 44 15 57 8 3 2 5 IO 120 34 11 32 7 8 7 12 23 I n CH2C12at 0 OC; 1 equiv of S K I 4 , 0.05 M starting concentration of each acetal. By capillary G C analysis using decane as an internal standard. Mean values from two experiments. CPrOductswere identified by independent synthesis. time. min
Table 11. SnCI,-Promoted Exchange of Acetals 13 and 14' acetal composition,bve % time, min acetal reqb % 13 14 15 16 17 18 0 ( 1 00) 52 48 5 81 13 12 15 11 24 23 60 86 12 12 IS 11 26 24 120 72 8 13 16 11 34 18 "In CH2C12at -70 OC; 1 equiv of SnCI,, 0.05 M starting concentration of each acetal. bBy capillary G C analysis using decane as an internal standard. CProducts15 and 16 were identified by independent synthesis, while 17 and 18 were characterized by GC-MS analysis.
limiting mechanisms for t h e Lewis acid promoted reaction of a nucleophile with an acetal: an SN1 reaction proceeding via an oxocarbenium ion intermediate (e.g., 1 3 4 in Scheme I) hydrogen-deuterium isotope effects were compared. Since first or an s N 2 p a t h ~ a y . ' ~ ,Mixed ~ * "aldehyde" acetals 1 (R2 = alkyl) introduced by Stephenson,lo this comparison has proven t o be a undergo SnC1,-promoted cyclization a t temperatures 30-60 O C powerfiil tool for establishing concert (or lack thereof) in ene below that required for the corresponding "formaldehyde" acetals reactions," including those of aldehyde and ketone e n ~ p h i l e s . ' ~ - ~ ~ (1, R2 = H).2 This observation argues strongly against an SN2 Nonequivalence of these isotope effects provides strong evidence pathway for the formation of A4-oxocenesfrom 5-hexenyl acetals for a stepwise process.'"I4 (2) The partitioning of 5-alkenyl acetals upon activation with this Lewis acid. The observed trends in acetal between exocyclization to form seven-membered-ring products reactivity suggest (at least in the case of mixed "formaldehyde" and endocyclization to form eight-membered-ring products was acetals) that ionization to an oxocarbenium ion might be rateexplored (Scheme 11). Since both modes of cyclization are devoid limiting.lsb Clearly, any comparison of kinetic and product hyof stereoelectronic constraints,I5 the ring size of the products drogen-deuterium isotope effects could shed light on the mechproduced should reflect the electronic bias of the alkene if cyanism of t h e ene cyclization step only if oxocarbenium ion forclization occurs in a stepwise fashion by way of cyclic carbenium mation were not rate-limiting. ion intermediates. Acetal Exchange. To pursue the facility with which acetals are activated for nucleophilic attack by SnCI4,we have examined Results and Discussion t h e SnC14-promoted exchange of alkoxy substituents in repreThe precise mechanism of activation of an acetal by a Lewis sentative formaldehyde and aldehyde acetals. Although exchange acid could impact the kinetic isotope experiments we planned. reactions of alcohols and acetals under protic conditions have Recent NMR studies by Denmark and co-workers have shown received considerable study, Lewis acid promoted exchange ret h a t t h e reaction of acetals with SnCI4at -78 O C does not form actions of acetals, to the best of our knowledge, have been little detectable amounts of an oxocarbenium (oxonium) ion, but rather i n v e ~ t i g a t e d . l ~The * ~ ~reactions we have examined are shown in two hexacoordinate complexes, R'CH(OR)2SnC14and [R'CHeqs 2 and 3, and t h e d a t a obtained are summarized in Tables I (OR)2]2SnCI,, depending upon ~toichiometry.~~.'~ There are two n . 4 H r rDCHaOMa
--
moted transformation of 5-hexenyl acetals t o A4-oxocenes. T w o experimental probes were employed: ( I ) Kinetic and product
6
(7) First suggested by Yang: Yang, N. C.; Yang, D. H.;Ross, C. B. J . Am. Cfiem.SOC.1959, 81, 133. (8) An alternate rationale would invoke a 1-oxabicyclo[4.2.0]octyl cation i (formed directly from 3 or from 4) as the immediate precursor of the A4-oxoceneproduct. Regioselectivity in this scenario would derive from the much better antarafacial orientation (with respect to the C 6 4 u bond) of the equatorial cyclohexyl hydrogen at C-5 than either of the cyclobutyl hydrogens at C-7. Evidence against the intermediacy of i was obtained in the SnC14promoted cyclization of the MEM ether of 5-hexen-1-01. This reaction gave, under kinetic conditions, a mixture of 4-chlorooxocane (iii) and A4-oxocene; 2-(2-~hloroethyl)tetrahydropyran(ii) was not formed.* The absence of ii would not be expected if i were present, since under kinetic acetolysis conditions i experiences opening by acetate anion 3 times faster at C-8 than at C-6.9 CI
SnCI.
7
+
R'OC~OR'
(2)
n.C,H, ,OCbOCH,CbOMo
7
PrCH(0Pr)s
MaCH(OPr),
13
SnCI,
+
.70 'C
M*CH(OEl)r
_c
15
+
PrCH(OEl),
+
16
RCH(OEt)(OPr) 17 R=Mo
14
18 R=Pr
(9) Paquette, L. A.; Scott, M. K. J. Am. Cfiem. SOC.1972, 94, 6760. (IO) Stephenson, L. M.; Grdina, M. J.; Orfanopoulos, M. Acc. Cfiem. Res. 1980, 13, 419. ( I I ) Dolbier, W. R., Jr. In Isotopes in Molecular Rearrangements; Buncel, E., Lee, C. C., Eds.; Elsevier: Amsterdam, 1975; Vol. 1, pp 51-57. Beak, P.; Berger, K . J. Am. Cfiem. Soc. 1980,102,3848. Seymour, C. A.; Greene, F. D. J . Org. Cfiem. 1982, 47, 5226. Cheng, C.-C.; Seymour, C. A,; Petti, M. A.; Greene, F. D.;Blount, J. F. J . Org. Cfiem. 1984,49, 2910. Starflinger, W.; Kresze, G.; Huss,K. J. Org. Cfiem. 1986, 51, 37. Orfanopoulos, M.; Foote, C. S.; Smonou, I . Tetrahedron Letr. 1987, 28. 15. Orfanopoulos, M.; Foote, C. S . J. Am. Chem. SOC.1988, 110, 6583. (12) Stephenson, L. M.; Orfanopoulos, M. J . Org. Cfiem. 1981,46,2200. (13) Snider, B. B.; Ron, E. J . Am. Cfiem. SOC.1985, 107, 8160. (14) Song, Z.; Chrisope, D. R.; Beak, P. J . Org. Cfiem. 1987, 52, 3938. (15) Baldwin, J. E. J . Chem. SOC.,Cfiem. Commun. 1976, 734. (16) For recent investigations of the structure of Lewis acid acetal complexes, see: (a) Denmark, S . E. In Selecfiuifies in Lewis Acid-Promoted Reoctions; Schinzer, D., Ed.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1989; Chapter 13. (b) Denmark, S . R.; Willson, T. M.; Almstead, N. G., submitted for publication.
(17) For an insightful study of the S ~ 1 & 2 question in Lewis acid promoted allylsilaneacetal cyclizations, see: Denmark, s. E.; Willson, T. M. J . Am. Cfiem. SOC.1989, 111, 3475. (1 8) (a) Mechanisms on the SN2extreme have been proposed to rationalize the stereochemical outcome of the addition of nucleophiles to chiral acetals; see, inter alia: Bartlett, P. A,; Johnson, W. S.; Elliott, J. D. J . Am. Cfiem. SOC.1983, 105, 2088. Mori, A.; Ishihara, K.; Arai, I.; Yamamoto, H.Tefrafiedron 1987, 43, 755. Reference 16b. (b) An s N 1 mechanism has been suggested for the trimethylsilyl triflate catalyzed reaction of enol silyl ethers and acetals: Murata, S.; Suzuki, M.; Noyori. R. Tetrahedron 1988,44,4259. (19) Denmark has reported that equilibration of the 1:l SnCI, complex of trans-4,5-dimethyl-l,3-dioxolanes with an oxocarbenium ion is rapid on the NMR time scale at -78 O C : Denmark, S.R. Lecture presented at the NATO Conference on Selectivity in Lewis Acid-Promoted Reactions, Glyfada-Athens, Greece, October 2-7, 1988. (20) (a) For an earlier study of acetal exchange, see: Gazizova, L. B.; Imashev, U. B.; Musavirov, R. S.; Kantor, E. A.; Zlotskii, S. S.; Kuzmichev, A. A.; Rakhmankulov, D. L. Zfi. Org. Kfiim. 1981, 17,275. (b) For a recent study of the relative reactivity of acetals in Lewis acid catalyzed reactions, see: von der Briiggen, U.;Lammers, R.;Mayr, H.J . Org. Cfiem. 1988,53, 2920.
A'- Oxocenes from Lewis Acid Promoted Cyclizations
J . Am. Chem. Soc., Vol. 112, No. 11, 1990 4401
Table 111. Measured Kinetic (Intermolecular) and Product (Intramolecular) lsotow Effects for the Formation of Oxocene 2fP conv,b temp time, SnCI,, acetal % OC min quiv concn, M 48 60 0.4 0.01 -20 -65
5
2.0
0.04
inter
67
k~tkd intra 1.64 f 0.05 1.64 & 0.05
60 0.4 0.01 48 1.69 i 0.10 -20 -50 IO 0.2 0.02 33 1.61 & 0.06 In CH2C12. bDetermined from the yield of isolated 20, using 33% as the yield for complete conversion;see ref 2. 'The mean * l a from two to three experiments.
phenyl)-A4-oxocene 27 occurs faster than acetal exchange (eq 5). Thus, when a 1:l mixture of acetals 25 and 26 was treated with BF3-OEt2 a t -40 O C and the reaction mixture analyzed by GLC-MS, only oxocene 27 was detected. ,SPh
and 11. Five of the eight possible products of eq 2 were quantified, while all four possible acetal exchange products of eq 3 were detected and quantified. The three missing formaldehyde acetals ( M e O C H 2 0 M e , M e O C H 2 0 C H 2 C H 2 0 M e , and MeOCH2CH20CH,0CHzCH20Me)are H 2 0 soluble and would have been "lost" in the aqueous layer prior to GLC analysis. Acetals 6 and 7 underwent exchange only when the temperature was raised to -10 to 0 OC, while exchange of acetals 13 and 14 was rapid at -70 OC. For the aldehyde-derived acetals, the equilibrium mixture of the six possible acetal products was formed within 5 min at -70 OC (Table 11). In this case mass recovery was high (SO-85%) and the symmetrical (13-16) and unsymmetrical (17 and 18) acetals were present in approximately their expected statistical ratios (l:2). Although the formaldehyde acetal exchange results are less significant, because of the lower mass balances obtained, the data in Table I demonstrate that a methoxymethyl (MOM) ether undergoes SnCI,-promoted exchange somewhat more rapidly than a methoxyethoxymethyl (MEM) ether. The close similarity between the conditions of the SnC14-promotedalkoxy-exchange reaction of formaldehyde acetals 6 and 7 and those of the cyclization of MOM or MEM ethers of 5-hexen-I -ols21 suggests that oxocarbenium ion formation is rate-limiting in the cyclizations of formaldehyde acetals to yield A4-oxocenes.22 Comparison of the data summarized in Table 11 with the cyclization reactions of related aldehyde-derived acetals reported in ref 2 suggests that acetal activation might be more rapid than the cyclization of mixed silyl acetals such as 19. Direct evidence to this end was obtained by carrying out the SnCI,-promoted cyclization of 19 (0.02 M in CHZCIz)in the presence of 1 equiv of acetal 13 (eq 4). This reaction afforded, as major products,
only
21 25
Kinetic and Product Hydrogen-Deuterium Isotope Effect Experiments. The results of the acetal-exchange experiments had several implications for our planned kinetic isotope effect (KIE) experiments: ( I ) To ensure that the cyclization step was at least partially rate-limiting, we would have to employ an aldehyde acetal initiator and the S-(trimethylsilyl)-5-hexenyl cyclization terminator. (2) Since the hydrogens at C-5 of the 4-oxocanyl cation intermediate 4 would be distereotopic if RZand RE # H, the two C-5 hydrogens would not strictly compete in an intramolecular competition experiment. If diastereoselectivity were high in loss of the C-5 hydrogen (or deuterium), the measured KIE from intramolecular competition could be equal to unity even in a stepwise process. (3) The magnitude of the observed KIE would be attenuated by the extent to which oxocarbenium ion formation were rate-limitir~g.~~ The precursors of the deuterium-labeled acetals 30 and 31 were prepared from aldehyde 28 or ester 29 by reduction with LiAID4. The isotopic purity of 30 (98% d2) and 31 (98% d,) was determined by 'H N M R integration; the former measurement used the I3C satellite of the OMe groups, of addeed p-methoxyanisole as an internal reference. 0 XK0i&OS~Bu1Me,
-
+
28 XsH
29 X.OYI
lo
2l R.Pr
the A4-oxocenes 20 and 21 and I,l-dipropoxyethane (15). Also detected in smaller amounts were acetals 17 and 18 and, at short reaction times (5 min), the 5-(trimethylsilyl)-5-hexenyl acetals 22-24. The structures of 21 and 24 were confirmed by independent synthesis, while acetals 22 and 23 were characterized by combined GLC-MS analysis. When the reaction of eq 4 was quenched after 5 min at -70 OC, oxOcenes M and 21 were present in a ratio of 3.5:1 ; after IO min this ratio was 1.7: I, and after 30 min it was 1.6:l. These results demonstrate that acetal exchange and cyclization of a 5-(trimethylsilyl)-5-hexenyl acetal take place at roughly comparable rates. A related experiment with cyclization substrates that contain the more nucleophilic vinyl sulfide moiety2 demonstrated that BF3.0Et2-promoted cyclization of 25 to form the 4-(thio(21) Typically conducted at -10 OC for several hours, MOM ethers cyclize somewhat faster than comparable MEM ethers2 (22) Consistent with this conclusion is the fact that SnCI,-promoted cyclizations (-10 "C) of mixtures of CHl=C(SiMe3)CH2( C H l ) 3 0 C H 2 0 C H 2 C H 2 0 M e and CH2=C(SiMe3)CD2(CH1),0CH20CH2CH20Meshowed no detectable hydrogen-deuterium isotope effect.
30 R'&=O 31 R ' d , #P.D
The results of conventional competition isotope effect measurements are summarized in Table 111. The product (intramolecular) and kinetic (intermolecular) isotope effects were found to be identical within our experimental precision. The value of 1.65 we observe is larger than what would be expected from secondary effects," yet smaller than isotope effects measured for the thermal ene reaction of oxomalonate with allylbenzene [(kH/kq)hler = (kH/kD),, = 3.31]12or observed by intramolecular competition in the MezAIC1-promoted reaction of various deuterated 2,3-dimethyl-2-butenes with f0rma1dehyde.I~ On the other (23) For example, if k H / k D= 2.5 and the initially formed oxocarbenium ion is present in low steady- state concentration and is partitioned equally between conversion of A4-oxoceneand reversal to the starting acetal, the observed k H / k Dwould be 1.75.
Blumenkopf et al.
4402 J . Am. Chem. Soc.. Vol. 112, No. 11, 1990 hand, the KlEs we observe are significantly larger than the very small kinetic and product isotope effects, (kH/kDz 1.1, measured for the SnCI,-promoted reaction of oxomalonate with allylbenzene. The kinetic (intermolecular) isotope effect of 1.65 that we observe rules out a mechanism in which a 4-oxocanyl cation intermediate is formed irreversibly in the rate-limiting step. The equivalence of the observed product and kinetic hydrogen-deuterium isotope effects provides clear evidence that the formation of the A4-oxocene occurs by a (concerted) process in which C-H bond cleavage accompanies C-C bond formation. The small magnitude of the observed kH/kD could result from oxocarbenium ion formation being partially rate-limitir~g.~~ Alternatively, the low hydrogen-deuterium isotope effect could arise from the nature of the intramolecular ene transition state.24 The concerted conversion of 3 5 would take place via a bicyclo[3.3.l]nonyl transition state (see 39) that would have a more acute C-H-O bond angle than that of related bimolecular ene reactions.25 Low primary isotope effects have been reported for acute angle proton-transfer reaction^.^^*^' We would also note that reversible formation of a complexz8 between the oxocarbenium ion and the vinylsilane prior to a concerted cycloaddition could also reduce the magnitude of the observed (kH/kD)ratio, as has recently been stressed by Beak.',
SiMe,
'
-
Competition between Forming Seven- and Eight-Membered Cyclic Ethers. The stereoisomeric 5-(trimethylsilyl)-5-decenyl
acetals 32 and 33 underwent cyclization at -1 5 "Cwhen treated with 2 equiv of SnC1, to give mixtures of the A4-oxocene 34 and the stereoisomeric 3-pentylideneoxepanes 35 and 36 (eq 7). The (E)-vinylsilane acetal 32 afforded oxOcene 34 as the major product (M35 = 2:l by GLC analysis), while the Z stereoisomer afforded the (E)-pentylideneoxepane 36 with high selectivity (3634= 17:l by GLC analysis). SiMe,
32
2. Iromrr
33
E-iiomer
34
35 2-lromrr 36
E-iromrr
A variety of electrophilic reactions of trisubstituted vinylsilanes proceed exclusively by bonding of the electrophile to the vinylic carbon bearing the silicon s u b s t i t ~ e n ta, ~result ~ ~ ~that ~ reflects the greater stability of a p-silyl secondary than an a-silyl tertiary carbenium ion. Thus, preponderant formation of oxOcene 34 from cyclization of 32 is a striking result. Since eight-membered rings are typically formed orders of magnitude more slowly than comparable seven-membered rings3' and neither mode of cyclization of 32 has any apparent stereoelectronic constraints, the predominant formation of oxocene 34 is inconsistent with the competitive formation of carbenium ions 37 and 38 from 32. However, this result could be accommodated in a mechanistic scheme wherein 34 is formed by a concerted ene reaction, which has a slightly lower energy barrier than competitive Prins cyclization of 32 to form the @-silyloxepanyl cation 38. That the E stereoisomer 33 cyclizes to afford primarily oxepane 36 is readily explicable in this (24) A type 111 intramolecular ene reaction using the systemization of 0ppolzer.h (25) A C-H-O angle of 154' is calculated for the concerted ene reaction of formaldehyde with propene: Loncharich, R. J.; Houk, K.N. J . Am. Chem. Soc. 1987, 109, 6947. (26) Liotta, D.; Saindane, M.; Waykole, L.; Stephens, J.; Grossman, J. J . A m . Chem. Soc. 1988, 110, 2667.
(27) For a theoretical treatment of nonlinear proton transfers and isotope effects, see: More OFerrall. R. A. J . Chem. Soc. B 1970, 785. (28) For a discussion of some of the possible intermediates, see: Reference 13. (29) Blumenkopf, T. A.; Overman, L. E. Chem. Reu. 1986.86, 857. (30) Fleming, 1.; Dunogues, J. Org. Reacr. 1989. 37, 57. (3 I ) Sicher, J. frog. Srereochem. 1982,3.202. Illuminati, G.; Mandolini, L. Arc. Chem. Res. 1981, 14, 9s.
37
38
39
mechanistic scenario, since the butyl group of 33 (which is cis related to the tethered oxocarbenium ion) would experience serious transannular interaction in an intramolecular ene transition state (e.g., 39).32*33 Conclusion
Two lines of evidence, (a) the equivalence of product and kinetic hydrogen-deuterium isotope effects, and (b) the absence of correlation of cyclization mode (endocyclic or exocyclic) with the stability of potential cyclic carbenium ion intermediates, are fully consistent with the formation of 4-(trimethylsilyl)-A4-oxocenes from 5-(trimethylsilyl)-5-alkenyl acetals occurring by a concerted intramolecular ene reaction. Experimental Section" CJX A M ~ Y S ~ SA. Hewlett-Packard 5790 chromatograph equipped with a 25-m, SP-2100 fused-silica capillary column and flame ionization detector was employed. Response factors were determined by triplicate analysis of two different molar ratios of decane and the component. The
response factors for 17 and 18 were interpolated from the values for the symmetrical acetals 13 and 14. Response factors for 9 and 10 were less accurate than others, since samples of these acetals (isolated by preparative GLC) contained 10% of other impurities. SnC14-PromotedExchange of Acetals 13 and 14. To a stirring solution of SnCI, (2.5 mL of a 1 M solution in CH2C12.2.5 mmol) and CH2C12 (17.5 mL) maintained at -68 OC (internal temperature) was added a solution of 13 (215 mg, 1.24 mmol), 14 (145 mg, 1.23 mmol), decane (177 mg, 1.23 mmol), and CH2C12( 5 mL). Aliquots ( 1 mL) were removed at 5 min, 1 h, and 2 h in a dry ice cooled syringe. Each aliquot was injected into a dry ice cooled vial containing excess Et,N. This solution was allowed to stir for 15 min and then saturated aqueous NaHCO, (1 mL) was injected into the vial. The organic layer was then analyzed by capillary GC. Results are presented in Table 11. Other exchange experiments were conducted in an identical fashion. l-Deuterio-4-[[(l,l-dimethyl)ethyldimethylsilyl]oxy]-l-butanol (40). To a mixture of LiAID, (Aldrich 98 atom % d, 920 mg, 22 mmol) in ether (30 mL) at 0 OC was added to a solution of 2835(2.0 g, 10 mmol freshly prepared by ozonolysis of the rerr-butyldimethylsilylether of 5-penten-1-01)and ether (20 mL). The reaction was heated at reflux for 3 h and then maintained at 23 OC for an additional 18 h. The reaction was quenched at 0 "C by the sequential dropwise addition of H 2 0 ( I mL), 15% NaOH (1 mL), and H 2 0 (3 mL). The resulting mixture was allowed to stir for 1 h, and the precipitated aluminum salts were removed by filtration and rinsed with ether. The combined filtrates were rinsed with brine, dried (K,CO,), and concentrated to afford alcohol 40 (1.5 g, 76%) as a clear colorless oil, which was used without further purification for the next reaction: 'H NMR (300 MHz, CDCI,) 6 3.68 (m, 3 H, CH20),2.54 (d, J = 12 Hz, 1 H, OH), 1.65 (m, 4 H), 0.90 (s, 9 H), 0.06 (s, 6 H); "C NMR (125 MHz, CDCI,) 6 63.6, 62.6 (t), 30.4, 30.1, 26.1, 18.5, 5.2; IR (film) 3360 (br), 2955, 2896, 2887, 1473, 1075, 1006,814, 661 cm-'; MS (CI) m / e 206 (MH). QDeuterio-l-[[(l,l-dimethyl)ethytai~thytsilyl]oxy~Qi~~~~ (41). A 1.5-g (7.3-mmol) sample of 40 was converted to the mesylate derivative in conventional fashion36and this intermediate was transformed to the corresponding iodide by heating at 50 OC with NaI ( 5 g, 30 mmol), NaHCO, (3 g, 30 mmol), and acetone (60 mL). The resulting colorless mixture was allowed to cool to 23 OC and was diluted with CH2C12(50 mL). This mixture was washed with H20, 20% aqueous Na2S03,and brine, and the organic extracts were dried (K2CO3) and concentrated. The residue was purified by column chromatography (silica gel, 3:l hexane-ethyl acetate) to afford 900 mg (50% from 40) of pure 41 as a (32) We have discussed in more detail elsewhere the general observation that terminal substituents that are cis to the tether of a nascent ring disfavor endocyclic cyclization^.^^ (33) Overman, L. E. Lecr. Hererocycl. Chem. 1985, 8, 59. (34) General experimental details are detailed in the preceding paper in this issue. (35) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron 1987,43, 731.
(36) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35, 3195.
A'- Oxocenes from Lewis Acid Promoted Cyclizations clear colorless oil: 'H NMR (250 MHz, CDCI,) 6 3.65 (t, J = 6.5 Hz, 2 H, CH20(TBS)), 3.24 (t, J = 6.2 Hz, 1 H, CHDI), 1.92 (m,2 H), 3.70 (m,2 H), 1.64 (m,2 H), 0.90 (s, 9 H), 0.08 (s, 6 H); IR (film) 2955, 2930,2894,2886, 1472,1256, 1072.837 cm-I; MS (CI) m / e 316 (MH). 4-(Deuterio-I-( l-ethoxyethoxy)-5-(trimethylsilyl)-!Lhexene (31) was prepared from 41 following the procedure employed2 to prepare the unlabeled analogue: MS (CI) m / e 246 (MH); MS (El, 26 eV) m / e 200.1546 (200.1581 calcd for ClIH22DOSi).The extent of deuteration (98%) was determined by integration of the signal for the allylic hydrogens at 8 2.1 relative to the signal for the acetal methine hydrogen at 8 4.7. 4,4-Dideuterio-I-(1-ethoxyethoxy)-5-(bimethylsilyl)-S-hexene (30). 1,I-Dideuterio-4-( I-ethoxyethoxy)butan-1-01was prepared by LiAID, reduction of methyl 4-(methoxymethoxy)butanoate, using the same general procedure employed to prepare 40.,' This intermediate was converted to 30 along the general lines employed to prepare the unlabeled 30 was homogeneous by capillary GC analysis and a n a l o g ~ e . ~ .Acetal ~' showed the following spectral properties: 'H NMR (300 MHz, CDCI,) 6 5.56 (d, J = 3.0 Hz, 1 H) and 5.32 (d, J = 2.9 Hz, 1 H, C(TMS)= CH2), 4.62 (s, 2 H, OCH20), 3.53 (t, J 6.4 Hz. 2 H, CH20), 3.36 (s, 3 H, OCH,), 1.63-1.56 (m,2 H), 1.50-1.45 (m,2 H), 0.08 (s, 9 H, SiMe,); I3C (125 MHz, CDCI,) 8 152.0, 124.0, 96.4, 67.6, 55.1, 35.4 (m),29.5, 25.5, -1.4; IR (film) 3050, 2956, 2900, 2850, 1744, 1438, 1250,848 cm-I; MS (CI) m/e 219 (MH); MS (El, 26 eV) m / e 201.1645 (201.1644 calcd for CI,H2,D2OSi).The deuterium content of 30 (1.8% residual ' H ) was determined by integrating the residual signals for the allylic methylene hydrogens (6 2.14) of 30 against a "C satellite peak of the methoxy group of added 1 ,Cdimethoxybenzene. Determinationof Kinetic Isotope Effects. Acetal 31 (or a 1:1 mixture of acetals 19 and 30) was treated with SnCI, under the conditions described in Table 111. The oxocene product 20 was isolated and the deuterium content at C-5 determined by triplicate integration of the C-5 vinylic hydrogen (6 6.0) vs the most downfield C-8 hydrogen (6 3.9). Isotope effects were then calculated: (kH/kD)intn= [(integral C-8 H) - (integral C-SH)]/(integral C-5 H); (kH/ko)inlcr= (integral C-5H)/ [integral C-8H - (integral C-5H)I. A typical procedure is summarized below. Cyclization of 31 at -20 OC with 0.4 Equivalent of SnQ. To a stirring solution of SnCI, (0.08 mL of a 1 M solution in CH2C12,0.08 mmol) and CH2CI2(18 mL) maintained at -20 OC (internal temperature) was added to a solution of 31 (35 mg, 0.14 mmol) and CH2CI2(2 mL). The reaction was maintained at -20 OC for 1 h and then quenched at -20 OC by the addition of Et,N (0.1 mL) and then a solution of 5% NaOH ( 5 mL). The organic layer was washed with brine (20 mL), dried (K2C03).and concentrated. The resulting oil was purified by preparative GC38(column temperature 80 "C) to provide oxocene 20. General Procedure for SnCl,-Promoted Cyclizations. Preparation of (Z)-3-Butylideneoxepane (35) and (E)-3-Butyl-4-(trimethylsilyl)3,6,7,8-tetrahydro-2H-oxocin (34) from (Z)-Vinylsilane Acetal 32. A ~~~
(37) Details are provided in the supplementary material. (38) Preparative GLC was conducted with a 4 ft X '/*-in. glass column packed with 10% SP-2330on 100/200 Suptlcoport The carrier flow rate was ca. SO mL/min.
J . Am. Chem. SOC..Vol. 112, No. 11. 1990 4403 mixture of vinylsilane acetal 32 (88 mg, 0.28 mmol) and dry CH2C12(2.8 mL) was added dropwise at -25 OC (bath temperature) over a I-h period to a solution of SnCI, (freshly distilled, 70 mL, 0.6 mmol) and dry CH2C12(2.8 mL). After 36 h at -15 "C, the reaction was quenched by pouring into excess 1 M NaOH solution. The organic layer was separated, the aqueous layer was extracted with pentane, and the combined organic extracts were dried (MgSO,) and concentrated. Purification of the residue by flash chromatography (silica gel, 99: 1 hexane-ether) gave 39 mg (66%) of a clear, colorless oil, which was shown by capillary GLC and 'H NMR analysis to be a 2:l mixture of 34 and 35. A pure sample of each compound was prepared by preparative GLC.38 Oxepane 3 5 ' H NMR (250 MHz, CDCIJ 6 5.22 (t, J = 7.0 Hz, 1 H, C=CH), 4.26 (br s, 2 H, OCH2C=C), 3.60 (m,2 H, C H 2 0 ) , 2.23 (m, 2 H, C==CCH2), 1.89 (m,2 H, C=CCH2), 1.59 (m,4 H), 1.29 (m, 4 H), 0.87 (t, J = 7.0 Hz, 3 H, Me); IR (CHCI,) 2820, 1450, 1070 cm-I; MS (El, 20 eV) m / e 168 (5), 11 1 (22), 59 (IOO), 43 (99); HRMS (20 eV) m/e 168.1513 (168.1514 calcd for C,,H2,0). Oxocene 34: 'H NMR (250 MHz, CDCI,) 6 6.12 (t, J = 8.0 Hz, 1 H, C=CH), 3.86 (dt, J = 4.0, 12.2 Hz, 1 H, C H 2 0 ) 3.45 (m,2 H, C H 2 0 ) , 3.34 (m, 1 H, CH20), 2.69 (app J = 6.8 Hz, 1 H, C=CCH), 2.26 (m, 2 H), 1.58 (m, 4 H), 1.27 (m,4 H), 0.87 (t, J = 6.7 Hz, 3 H, Me); IR (CHCIJ 2920, 1590, 1457, 1243, 11 12,830 cm-I; MS (El, 20 eV) m / e 241 (MH, I ) , 240 (M, 6), 225 (9), 183 (2), 73 (67), 59 (IOO), 43 (69); HRMS m/e 240.1901 (240.1909 calcd for C14H280Si), 225.1677 (225.1674 calcd for CI3H,OSi, M - Me). Preparation of (E)-3Butylideneoxepane (36) and (E)-3-Butyl-4(trimethylsilyl)-3,6,7,8-tetrahydro-2H-oxocin(34) from (E)-Vinylsilane Acetal 33. Vinylsilane 33 (102 mg, 0.322 mmol) was treated with SnCI, (80 mL, 0.70 mmol) at -15 OC for 72 h as described for the cyclization of 32. Purification of the crude product by flash chromatography (24:l hexane-ether) gave 36 mg (63%) of a clear, colorless oil, which capillary GLC and 'H NMR analysis showed to be a 17:1:2 mixture of 36,34,and an unidentified material. An analytical sample of 36 was obtained by preparative GLC? 'H NMR (250 MHz, CDCIJ 6 5.26 (t, J = 7.0 Hz, 1 H, C=CH), 4.10 (s, 2 H, OCH2C=C), 3.78 (m,2 H, C H 2 0 ) , 3.72 (m, 2 H, C H 2 0 ) , 2.28 (m, 2 H, C = C C H 2 ) , 2.01 (m,2 H, C = C C H 2 ) , 1.61 (m, 2 H), 1.31 (m, 4 H), 0.89 (t, J = 7.0 Hz, 3 H, Me); irradiation of the vinylic hydrogen at 8 5.26 resulted in a large NOE enhancement for the C-2 methylene hydrogens at 6 4.10 IR (CHCI,) 2918, 1448, 1103 cm-I; MS (El, 30 eV) m / e 169 (MH, 3), 168 (M, 19), 125 (20), 112 (76), 82 (80), 69 (loo), 56 (99), 43 (87); HRMS m / e 168.1499 (168.1514 calcd for CI,H2,O).
Acknowledgment. This research was supported by NSF Grant CHE-86-1845 1. NMR and mass spectra were determined with spectrometers purchased with the assistance of NSF Shared Instrumentation Grants. We wish to acknowledge Dr. Andrew S . Thompson for the experiments reported in footnote 22, Professor Scott Denmark for sharing unpublished data, and Professor Peter Beak for his insightful discussion. Supplementary Material Available: Experimental details and characterization data for preparation of 42-48 ( 5 pages). Ordering information is given on any current masthead page.
